A patient with severe fever with thrombocytopenia syndrome and hemophagocytic lymphohistiocytosis-associated involvement of the central nervous system

Severe fever with thrombocytopenia syndrome (SFTS), a severe infectious disease caused by novel bunyavirus, SFTS virus (SFTSV), is endemic to China, Korea, and Japan. Most SFTS patients show abnormalities in consciousness. Pathological findings in the central nervous system (CNS) of SFTS patients are not reported. A 53-year-old Japanese man was admitted to Uwajima City Hospital with an 8-day history of fever and diarrhea. Laboratory tests revealed leukopenia, thrombocytopenia, and liver enzyme elevation. He was diagnosed as having severe fever with thrombocytopenia syndrome (SFTS) following detection of the SFTSV genome in his blood. Bone marrow aspiration revealed hemophagocytic lymphohistiocytosis. He suffered progressive CNS disturbance and died on day 13 from onset of first symptoms. The SFTSV genome load in blood and levels of certain cytokines increased over the disease course. Necrotizing lymphadenitis with systemic lymphoid tissues positive for nucleocapsid protein (NP) of SFTSV was revealed by immunohistochemical (IHC) analysis. SFTSV-NP-positive immunoblasts were detected in all organs examined, including the CNS, and in the vascular lumina of each organ. Parenchymal cells of all organs examined were negative for SFTSV-NP on IHC analysis. Microscopic examination of the pons showed focal neuronal cell degeneration with hemosiderin-laden macrophages around extended microvessels with perivascular inflammatory cell infiltration and intravascular fibrin deposition. Autopsy confirmed this patient with SFTS was positive for systemic hemophagocytic lymphohistiocytosis including in the CNS. This patient's neurological abnormalities may have been caused by both functional and organic abnormalities. These novel findings provide important insights into the pathophysiology of SFTS.     

Pathophysiology of severe fever with thrombocytopenia syndrome and development of specific antiviral therapy

Severe fever with thrombocytopenia syndrome (SFTS) caused by SFTS virus (SFTSV), a novel phlebovirus, was reported to be endemic to central and northeastern PR China and was also to be endemic to South Korea and western Japan. SFTS is an emerging viral infection, which should be categorized as a viral hemorrhagic fever disease as Crimean-Congo hemorrhagic fever (CCHF) is caused by CCHF virus. SFTS is a tick-borne viral infection. SFTSV is maintained between several species of ticks and wild and domestic animals in nature. Patients with SFTS show symptoms of fever, general fatigue, and gastrointestinal symptoms such as bloody diarrhea. The severely ill SFTS patients usually show gastrointestinal hemorrhage and deteriorated consciousness. The case fatality rate of SFTS ranges from 5 to 40%. Pathological studies on SFTS have revealed that the mechanisms behind the high case fatality rate are virus infection-related hemophagocytic syndrome associated with cytokine storm, coagulopathy due to disseminated intravascular coagulation causing bleeding tendency, and multi-organ failure. Favipiravir was reported to show efficacy in the prevention and treatment of SFTSV infections in an animal model. A clinical study to evaluate the efficacy of favipiravir in the treatment of SFTS patients has been initiated in Japan. SFTSV is circulating in nature in PR China, Korea, and Japan, indicating that we cannot escape from the risk being infected with SFTSV. The development of specific therapy and preventive measures is a pressing issue requiring resolution to reduce the morbidity and mortality of SFTS patients.     

Seroprevalence of severe fever with thrombocytopenia syndrome (SFTS) virus antibodies in humans and animals in Ehime prefecture,Japan, an endemic region of SFTS

Severe fever with thrombocytopenia syndrome (SFTS) was first identified as an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) in China and has also been found to be endemic to Japan and South Korea, indicating that SFTS is of great concern in East Asia. The aim of the present study was to determine the seroprevalence of SFTSV antibodies in humans and animals in SFTS-endemic regions of Japan. One of 694 (0.14%) healthy persons over 50 years of age and 20 of 107 (18.7%) wild and domestic animals in Ehime prefecture of western Japan were determined to be seropositive for SFTSV antibodies by virus neutralization test and ELISA, respectively. The seropositive person, a healthy 74-year-old woman, was a resident of the southwest part of Ehime prefecture engaged in citriculture and field work. This woman's sample exhibited neutralizing activity against SFTSV although she had neither a clear experience with tick bites nor SFTS-like clinical illness. These findings indicate that most people living in the endemic regions are not infected with SFTSV and suggest that most of the SFTS patients reported so far do not reflect the tip of an iceberg of people infected with SFTSV, but at the same time, that SFTSV infection does not always induce severe SFTS-associated symptoms. These findings also suggested that SFTSV has been maintained in nature within animal species and ticks.     

Retrospective study on the possibility of an SFTS outbreak associated with undiagnosed febrile illness in veterinary professionals and a family with sick dogs in 2003

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick-born disease and its animal-to-human transmission has come to attention recently. During our sero-survey of SFTS virus (SFTSV) among veterinary professionals in 2018, a veterinarian and his assistant working in an animal hospital were tested positive by enzyme-linked immunosorbent assay (ELISA). An additional survey implied a cluster of SFTS cases in which four more people, a family who brought two sick dogs to the animal hospital in 2003, were involved. This study aimed at assessing the possibility of animal-to-human transmission of SFTSV in this cluster.MethodsRetrospective interviews were performed with the owner family of the dogs and their clinical records were obtained from each hospital. SFTSV-IgG were tested by ELISA and virus neutralization test using the sera collected from them in 2018.ResultsThe interviews revealed that a total of six people, the two veterinary professionals and the owner family who took care of the sick dogs, suffered from SFTS-like symptoms in the same period of time in 2003. All patients did not have tick bite before the onset and all suspected causative agents were excluded by laboratory tests. The serological tests in this study revealed the four owner family members were all positive for SFTSV antibodies.ConclusionsConsidering the extremely low seroprevalence of SFTSV antibodies among inhabitants of the region, the existence of SFTSV antibodies in all these six people presents a possibility that they were involved in an SFTS outbreak originated in the sick dogs in 2003.     

Several catechins and flavonols from green tea inhibit severe fever with thrombocytopenia syndrome virus infection in vitro

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever caused by SFTS virus (SFTSV). The mortality rate of SFTS is pretty high, but no vaccines and antiviral drugs are currently available.MethodsThe antiviral effects of six green tea-related polyphenols, including four catechins and two flavonols, on SFTSV were evaluated to identify natural antiviral compounds.ResultsPretreatment with all polyphenols inhibited SFTSV infection in a concentration-dependent manner. The half-maximal inhibitory concentrations of (?)-epigallocatechin gallate (EGCg) and (?)-epigallocatechin (EGC) were 1.7–1.9 and 11–39 μM, respectively. The selectivity indices of EGCg and EGC were larger than those of the other polyphenols. Furthermore, pretreatment with EGCg and EGC dose-dependently decreased viral attachment to the host cells. Additionally, the treatment of infected cells with EGCg and EGC inhibited infection more significantly at a lower multiplicity of infection (MOI) than at a higher MOI, and this effect was less effective than that of pretreatment. Pyrogallol, a trihydroxybenzene that is the structural backbone of both EGCg and EGC, also inhibited SFTSV infection, as did gallic acid.ConclusionsOur study revealed that green tea-related polyphenols, especially EGCg and EGC, are useful as candidate anti-SFTSV drugs. Furthermore, the structural basis of their antiviral activity was identified, which should enable investigations of more active drugs in the future.     

发热伴血小板减少综合征的血象及骨髓象分析

目的研究发热伴血小板减少综合征(SFTS)患者的血象和骨髓象特点。方法回顾性总结分析30例SFTS确诊患者的资料。结果 SFTS布尼亚病毒(SFTSV)感染机体可导致外周血白细胞、血小板减少,网织红细胞减低,并出现异型淋巴细胞,在疾病极期-晚期骨髓增生减低,造血细胞明显受抑,并出现较多噬血细胞。结论外周血和骨髓检测对SFTS的诊断、预后判断有一定的临床意义。     

Caffeic acid,a coffee-related organic acid,inhibits infection by severe fever with thrombocytopenia syndrome virus in vitro

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) causes tick-borne hemorrhagic fever in East Asia. The disease is characterized by high morbidity and mortality. Here, we evaluated the effects of caffeic acid (CA), a coffee-related organic acid with antiviral effects, against SFTSV infection. CA dose-dependently inhibited SFTSV infection in permissive human hepatoma Huh7.5.1–8 cells when SFTSV was added into the culture medium with CA. However, quinic acid (QA), another coffee-related organic acid, did not inhibit SFTSV infection. The 50% inhibitory concentration (IC₅₀) of CA against SFTSV was 0.048 mM, whereas its 50% cytotoxic concentration was 7.6 mM. The selectivity index (SI) was 158. Pre-incubation of SFTSV with CA for 4 h resulted in a greater inhibition of SFTSV infection (IC₅₀ = 0.019 mM; SI = 400). The pre-incubation substantially decreased viral attachment to the cells. CA treatment of the SFTSV-infected cells also inhibited the infection, albeit less effectively. CA activity after cell infection with SFTSV was more pronounced at a low multiplicity of infection (MOI) of 0.01 per cell (IC₅₀ = 0.18 mM) than at a high MOI of 1 per cell (IC₅₀ > 1 mM). Thus, CA inhibited virus spread by acting directly on the virus rather than on the infected cells. In conclusion, CA acted on SFTSV and inhibited viral infection and spread, mainly by inhibiting the binding of SFTSV to the cells. We therefore demonstrated CA to be a potential anti-SFTSV drug for preventing and treating SFTS.     

L-DOPA,a treatment for Parkinson's disease,and its enantiomer D-DOPA inhibit severe fever with thrombocytopenia syndrome virus infection in vitro

Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of 16.2–47% has been reported. Vaccines and antivirals that are effective against SFTS virus (SFTSV) are not yet available in clinical practice. We previously showed that o-dihydroxybenzene is the important chemical core structure for anti-SFTSV activity. In this study, we evaluated the anti-SFTSV efficacy of 3-Hydroxy-L-tyrosine (L-DOPA), a treatment for Parkinson's disease and its enantiomer, 3-hydroxy-D-tyrosine (D-DOPA), both of which have an o-dihydroxybenzene backbone. SFTSV was preincubated with L- or D-DOPA and then inhibition of viral infection as well as viral attachment to host cells were evaluated by viral quantification. Both L- and D-DOPA inhibited SFTSV infection in a dose-dependent manner, mainly by blocking viral attachment to host cells. The half-maximal inhibitory concentration (IC₅₀) of L-DOPA was 4.46–5.09 μM. IC₅₀ of D-DOPA was 4.23–6.72 μM. IC₅₀ of L-DOPA is very close to its maximum blood concentration after oral administration as a therapy for Parkinson's disease. D-DOPA, which IC₅₀ was almost the same as that of L-DOPA, might not cause side effect. Thus, our present study demonstrated that L- and D-DOPA are potentially useful candidates for anti-SFTSV drugs.     

Ceftazidime encephalopathy developed without the elevation of cerebrospinal fluid concentration of ceftazidime: A case report of two cases

BackgroundCeftazidime encephalopathy is reported to be caused by the repeated administration of ceftazidime in patients with renal impairment because of the high serum concentration of ceftazidime. Ceftazidime encephalopathy has been considered to be caused by the elevation of the cerebrospinal fluid (CSF) concentration. However, as no reports have measured CSF concentrations, the relationship with ceftazidime encephalopathy and CSF concentration has not been clarified.Case presentationCase 1: An 80-year-old Japanese man under a combination therapy with peritoneal dialysis and hemodialysis, who had been treated for a cellulitis with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was only under 0.1 μg/mL. Case 2: An 88-year-old Japanese man with chronic kidney disease, who had been treated for a urinary tract infection with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was within the therapeutic range. However, his serum and CSF concentration of quinolinic acid was markedly increased.ConclusionsPatients with renal failure are more likely to develop ceftazidime encephalopathy. We need to pay attention to the dosage of ceftazidime and to the appearance of neurological symptoms. Ceftazidime encephalopathy was considered to be caused by the high CSF concentration, but it could be caused by quinolinic acid as neurotoxic substance.     

One-year-old boy with refractory Listeria monocytogenes meningitis due to persistent hypercytokinemia

We had a case of Listeria monocytogenes (LM) meningitis complicated with hypercytokinemia and hemophagocytic lymphohistiocytosis in a healthy 22-month-old boy. He was admitted to our hospital with a fever, vomiting, mild consciousness disturbances, and extraocular muscle paralysis. Magnetic resonance imaging (MRI) revealed bilateral deep white matter lesions. After receiving ampicillin, meropenem, and gentamicin, his cerebrospinal fluid (CSF) culture results turned negative on the third day of hospitalization. However, the fever intermittently persisted, and it took approximately 40 days to completely resolve. During this period, various inflammatory cytokine levels, particularly neopterin, in the blood and CSF remained elevated. Therefore, long-term administration of corticosteroids in addition to antibiotics was required. The use of dexamethasone appeared to be effective for neurological disorders such as consciousness disturbance and extraocular muscle paralysis associated with abnormal brain MRI findings. LM meningitis may present with encephalopathy and persistent fever due to hypercytokinemia. In such cases, corticosteroid therapy should be considered.     

Analysis of the risk factors and prognosis for severe fever with thrombocytopenia syndrome associated encephalopathy

ObjectiveSevere fever with thrombocytopenia syndrome (SFTS) is frequently associated with neurological injury, but there are currently few relevant studies. The goal of this study was to look at the risk factors for SFTA-associated encephalopathy (SFTSAE) and the short- and long-term prognosis of such patients.MethodsWe retrospectively studied 145 patients with SFTS who were treated at our hospital between May 2019 and November 2021. Clinical characteristics were collected, and patients were divided into two groups based on whether there was neurological injury during the disease: SFTSAE group and non-SFTSAE group. Univariate analysis was used to compare the differences in clinical data and outcomes between two groups, and multivariate Logistic regression analysis was used to reveal the independent risk factors for SFTSAE, and the predictive efficacy was assessed using the receiver operating characteristic (ROC) curve. Furthermore, survivors of SFTSAE were contacted by phone 6 months after discharge to assess the case fatality rate and quality of life.ResultsThe prevalence of SFTSAE was 22.7% (33/145). Bleeding symptoms, D-dimer level and blood amylase level were all independent risk factors for SFTSAE (P < 0.05). The combined AUC of these three factors was 0.969. Patients with SFTSAE had a 45.4% in-hospital mortality rate, and survivors had a largely normal quality of life after discharge.ConclusionPatients with SFTSAE frequently have multiple organ dysfunction, a high mortality rate, and a favorable long-term prognosis for survivors. Clinical manifestations of bleeding symptoms, elevated serum amylase, and elevated D-dimer were all independent risk factors for SFTSAE.     

A case of postmalaria neurological syndrome in Japan

Several neurological complications are associated with severe falciparum malaria. Indeed, some patients experience a neurological syndrome after complete recovery from Plasmodium falciparum infection. Particularly, postmalaria neurological syndrome (PMNS) is a self-limiting post-infective encephalopathy that occurs within 2 months after an episode of P. falciparum infection. We describe the case of a 54-year-old Japanese man who was readmitted to our hospital with incoherent speech and markedly disturbed and uncooperative behavior after a high-grade fever that occurred after an earlier adequately treated severe P. falciparum infection. Peripheral blood smears were repeatedly negative for malaria parasites, no organisms were detected in the cerebrospinal fluid, and no hallmark lesions of acute disseminated encephalomyelitis were depicted by brain magnetic resonance imaging. The neuropsychiatric symptoms were thought to be due to PMNS. The etiology of PMNS remains unclear, but it could be mediated by an immunological mechanism and could possibly be caused by mefloquine treatment. PMNS must be considered when characteristic neurological signs and symptoms such as psychotic or acute confusional episodes, general convulsions, and tremor occur after recovery from severe P. falciparum infection treated with oral mefloquine. This is the first reported case of suspected PMNS in Japan.     

Can therapeutic plasma exchange be life-saving in life-threatening manganese intoxication?

We present a pediatric patient presenting with life-threatening severe neurological signs, chronic liver disease, and manganese intoxication who fully recovered from neurological signs and symptoms following chelation therapy and therapeutic plasma exchange (TPE). A 13-year-old female patient was admitted with abdominal pain. Loss of consciousness and decorticate posture (GCS;M:1,V:1,M:3) developed at the 5th hour of admission. She admitted to the intensive care unit intubated. No infectious etiology that could explain acute encephalopathy was detected. Abdominal ultrasound showed granular, heterogeneous liver parenchyma suggesting chronic hepatic disease, and TPE was administered for two days since Wilson's disease and autoimmune encephalitis could not be ruled out. Cranial MRI findings were consistent with a diagnosis of manganese intoxication. On Day 3 after admission, chelation therapy and TPE were administered based on a diagnosis of manganese intoxication. Blood manganese levels at admission, day 2, and day 5 were 46, 22, and 17.5 μg/dL (NR:4.7–18.3). Control MRI results showed reduced intracranial manganese deposition, and the patient regained full consciousness. TPE as an adjunct to chelation therapy may represent an effective therapeutic option in manganese intoxication.     

2018-2020年浙江省舟山市蜱类分布及发热伴血小板减少综合征病例调查

  目的   了解浙江省舟山市蜱类季节消长规律、种群分布情况及发热伴血小板减少综合征病例发生情况,分析其相关性。  方法   2018 — 2020年在舟山市定海、普陀、岱山、嵊泗区（县）发热伴血小板减少综合征确诊病例发生地周围采用布旗法收集游离蜱,采用体表检蜱法收集寄生蜱,运用荧光反转录酶聚合酶链式反应（RT-PCR）检测新型布尼亚病毒核酸。采用Excel 2017软件汇总数据,用SPSS 19.0 软件进行数据分析。  结果  2018 — 2020年共捕获游离蜱612只,以长角血蜱为主（83.82%）,镰形扇头蜱次之（14.05%）。 共有发热伴血小板减少综合征病例20例,发病基本集中在岱山县。 在确诊病例发生地周围共捕获51只游离蜱,86只寄生蜱,均为长角血蜱,经检测新型布尼亚病毒核酸均为阴性。  结论  舟山市优势蜱种为长角血蜱,农村外环境是蜱的主要生活环境,每年5 — 9月是蜱的活动高峰时间,发热伴血小板减少综合征病例的发生与蜱的活动高峰密切相关。     

Nervous system involvement in hemorrhagic fever with renal syndrome

The authors of the article describe two cases of hemorrhagic fever with renal syndrome (HFRS) with prevalence of signs of nervous system involvement. The first case was a 40-year-old woman with moderate HFRS, who developed Guillain-Barre syndrome of axonal-demyelinating polyneuropathy. An important observation was the absence of hemorrhagic or renal syndrome; combined therapy including plasmapheresis was successful. The second case demonstrated polymorphism of HFRS clinical manifestations with prevalence of neurological symptoms, which consisted in encephalopathy and no renal failure signs; hemorrhagic syndrome was moderate. In both cases the diagnosis was confirmed by elevated titer of antibodies to HFRS virus, belonging to the group of hantaviruses.     

A 4-year-old girl with clinically mild encephalopathy with a reversible splenial lesion associated with rotavirus infection

Rotavirus is a common cause of severe gastroenteritis in children. It is known that rotavirus gastroenteritis may be accompanied by neurological manifestations, including encephalitis/encephalopathy and seizures. We report a case of a 4-year-old girl with clinically mild encephalopathy with a reversible splenial lesion associated with rotavirus infection. She was admitted to our hospital because of reduced level of consciousness, seizures, diarrhea, and vomiting. Fecal rotavirus antigen testing was positive. Cell counts in the cerebrospinal fluid (CSF) were normal. She had a normal serum sodium level on admission. Brain computed tomography showed no cerebral edema. However, electroencephalography showed generalized high-voltage slow waves, and diffusion-weighted magnetic resonance imaging demonstrated a transient abnormality in the splenium of the corpus callosum. We diagnosed clinically mild encephalopathy with a reversible splenial lesion associated with rotavirus infection. She recovered well and exhibited no neurological sequelae. Rotavirus RNA and antigen were not detected in the CSF, suggesting that the reversible splenial change was caused by indirect effects on the central nervous system subsequent to viral infection. Her normal serum sodium level indicates that this change can occur without hyponatremia.     

Steroid pulse therapy for severe fever with thrombocytopenia syndrome patients may not improve prognosis: Retrospective analysis with overlap weighting using a national inpatient database

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus. Effective treatment for SFTS has not been established, but steroid pulse therapy is often used. This study aimed to verify whether steroid pulse therapy for SFTS improves prognosis or not.MethodsData of SFTS patients were obtained from the Japanese Diagnosis Procedure Combination Database from April 2013 to March 2021. Patients treated with steroid pulse therapy were compared with untreated patients, using overlap weighting and traditional multivariable regression analysis to evaluate the impact of steroid pulse therapy on prognosis.Results412 SFTS patients were included in this study, and 66 (16%) underwent steroid pulse therapy within 3 days of admission and were allocated to the steroid pulse therapy group. After overlap weighting, patients in the steroid pulse therapy group had a significantly higher in-hospital mortality rate than patients in the control group (31.1% vs. 20.5%; difference: +10.6%; 95% confidence interval: +2.2% to +19.0%). There were no statistically significant differences in hospitalization cost and length of hospital stay between the two groups. The results of the sensitivity analysis using traditional multivariable regression were similar to those of the main analysis.ConclusionIn the analysis of SFTS patients using the Japanese Diagnosis Procedure Combination inpatient data, steroid pulse therapy did not improve patient prognosis. The evidence does not support the universal use of steroid pulse therapy in patients with severe SFTS.     

新型冠状病毒相关成人急性坏死性脑病1例报告

<正>急性坏死性脑病（acute necrotizing encephalopathy, ANE）进展迅速，多见于婴幼儿，成人罕见。患者多有前驱病毒感染史，临床上以癫痫发作、意识障碍（迅速进展至昏迷）和多器官功能衰竭为主要表现，头颅影像学表现以对称性、多灶性损害为主要特征。本文报告1例新型冠状病毒相关成人ANE，为临床实践提供参考。     

Acute focal bacterial nephritis characterized by acute encephalopathy with biphasic seizures and late reduced diffusion

Acute focal bacterial nephritis (AFBN) is a localized bacterial infection of the kidney presenting as an inflammatory mass, and some patients show deterioration of clinical condition with neurological symptoms. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a syndrome that is characterized by biphasic seizures and impaired consciousness with reduced diffusion in the subcortical white matter on magnetic resonance imaging, typically observed between days 3 and 9 after clinical onset. Although AFBN sometimes causes neurological symptoms, no cases of AFBN with AESD have been reported, and no studies have presented the cytokine profiles of patients with a severe form of acute encephalopathy with AFBN. We report here a very rare case involving a 6-month-old boy who developed AFBN due to Enterococcus faecalis with both the clinical and radiological features of AESD. In our patient, serum interleukin (IL)-6, IL-10, and interferon (IFN)-γ levels markedly increased on admission, and on day 4, only IL-6 levels significantly increased in the cerebrospinal fluid (CSF). These results suggest that high serum cytokines are produced locally in response to AFBN and elevated IL-6 levels in CSF may have neuroprotective roles.